1. Field of the Invention
The present disclosure provides a series of compounds which exhibit isoform selective inhibition of Glucose-related protein 94 (Grp94), a homologue of the cytoplasmic Heat shock protein 90 (Hsp90) that is localized to the endoplasmic recticulum. Through Grp94 inhibition, these compounds are likely to manifest anti-cancer, anti-inflammatory, anti-metastasis, and immunosuppressive activities, in addition to exhibiting properties beneficial to the management of neurodegenerative diseases, and diabetes.
2. Description of the Related Art
Hsp90 chaperones contain an N-terminal ATP binding site that has been effectively targeted by competitive inhibitors. Although Hsp90 inhibition has garnered tremendous attention in drug development for multiple disease states and numerous companies are in late-stage clinical development, no isoform selective inhibitor has yet been discovered. Despite the development of a number of Hsp90 inhibitors, none to date have been designed to bind specifically to just one of the four mammalian Hsp90 paralogs, which are cytoplasmic Hsp90α and β, ER Grp94, and mitochondrial Trap-1. Multiple detriments are associated with current Hsp90 inhibitors, which in many cases result from the non-selective inhibition of all four Hsp90 isoforms. To date, all known disruptors of Hsp90 are pan-inhibitors, that is, they inhibit all isoforms.
Although Hsp90 represents a promising therapeutic target for the treatment of cancer and other diseases, unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms.
Rationale to develop isoform selective inhibitors is highly desirable and to the best of our knowledge has not been reported.
Grp94 is an isoform of heat shock protein 90 kDa (Hsp90) localized to the endoplasmic reticulum. Grp94 is responsible for the maintenance of cell adhesion proteins and the trafficking of numerous receptors to the cell membrane. Through inhibition of Grp94, this process is halted. GRP94 is present at elevated levels in numerous cancers and several GRP94 client proteins have been recognized. For example, see McLaughlin and Vandenbroeck. Brit. J. Pharmacol. 2011, 162, 328-345, which is incorporated herein by reference.
The anti-cancer effects of Hsp90 inhibition have driven the development of potent antagonists. Among the first Hsp90 inhibitors to be identified were the natural product ansamycin antibiotics Geldanamycin (Gdm) and Radicicol (Rdc). The scaffolds of these ansamycins and the natural ligand ATP were exploited for inhibitor design. Gdm has also been used as a tool to better understand the quaternary structure and regulatory roles of GRP94. Chu et al., 2006, Protein Sci., 15:1260-1269; Chiosis et al., Biorg. Med. Chem. Lett 2006; 16:3529-32. A chimeric Hsp90 inhibitor, Radamide, was previously developed from the structures of Gdm and Rdc. Clevenger and Blagg, Org. Lett. 2004; 6: 4459-62. Various radamide analogs have been previously described. See for example, Hadden and Blagg, 2009, J. Org. Chem., 74(3):4697-4704, which is incorporated herein by reference.
To understand differences in how pan-Hsp90 inhibitors interact with the Grp94 and Hsp90 ATP binding site, Immormino et al., 2009 solved the co-crystal structures of the radicicol-geldanamycin chimera Radamide bound both to yeast Hsp82 and Grp94. The Radamide co-crystal structures revealed distinct ligand poses that exploit differences in the ATP binding sites of Hsp90 and GRP94. Direct binding assays with Radamide revealed disparate affinities for the two Hsp90 paralogs. Taken together, these results demonstrate that Grp94 and Hsp90, though very similar, interact with a selection of Hsp90 inhibitors in different manners. See Immormino et al., 2009, J. Mol. Biol., 388(5):1033-1042, which is incorporated herein by reference.
The discovery of more selective Grp94 selective inhibitors is highly desirable and is predicted to have implications in both drug development as well as the treatment of multiple disease states including cancer, inflammation, neurodegeneration and diabetes. Until this disclosure, the only methods for selective Grp94 disruption reported have been through gene silencing and siRNA procedures. It was previously unknown whether a Grp94 selective inhibitor could be constructed.
The disclosure provides rationale and design of scaffolds that exhibit selective Grp94 inhibition. For example, the discovery of the first isoform selective inhibitors of Grp94, some of which exhibit greater than 100-fold selectivity for Grp94 over cytosolic Hsp90, is herein disclosed.